Radiolabeled biochemically active groups are of increasing interest in the field of diagnostic imaging. Essentially, a biochemically active group is a metabolic substrate or inhibitor or a molecule with an affinity for a specific receptor. Knowledge of certain properties, such as receptor binding or metabolism, involving various biochemically active groups suggest, at least in theory, that radiolabeled versions of such groups may be useful in imaging the function and/or condition of a specific organ, rather than merely the blood flow to that organ. An effective complex is one wherein the radionuclide and biochemically active group are stably bound to each other and further, wherein the complex behaves, or is "taken up" substantially as the free biochemically active group would behave.
Numerous attempts to prepare effective complexes of this nature have been reported. For example, Fowler et al. (Int. J. Appl. Radiat. Isot., 1986, 27, p. 663-8, "2-deoxy-2[.sup.18 F]fluoro-D-glucose for metabolic studies: current status") have investigated the radiolabeling of the metabolic substrate, deoxyglucose, with .sup.18 F for use in diagnostic imaging of the brain. Brain and lung imaging has also been attempted by Winchell et al. (J. Nucl. Med., 1980, 21, p. 940-6, "Development of I-123-Labeled Amines for Brain Studies: Localization of I-123 Iodophenylalkyl Amines in Rat Brain" and J. Nucl. Med., 1980, 21, p. 947-52, "N-Isopropyl-[.sup.123 I]p-Iodoamphetamine: Single-Pass Brain Uptake and Washout; Binding to Brain Synaptosomes; and Localization in Dog and Monkey Brain") who report radiolabeling of amphetamines, known to interact with specific receptors, with .sup.123 I. The radio-iodinated amphetamine known as "Spectamine" is currently marketed for brain imaging.
Free fatty acids are primary substrates of the normally perfused myocardium and, as such, are viewed as potentially useful in studying free fatty acid metabolism via the beta-oxidation pathway. Accordingly, van der Wall et al. (Eur. J. Nucl. Med., 1986, 12, p. S11-S15, "Myocardial imaging with radiolabeled free fatty acids: Applications and limitations") have studied free fatty acid labeled with positron emitting isotopes, e.g., .sup.11 C, .sup.13 N and .sup.15 O, as well as with the gamma-emitting isotope .sup.123 I. Additionally, Jones et al. (J. Nucl. Med., 1988, 29(5.sub.), p. 935, "Synthesis of a Novel [Tc99m]-Diaminodithiol-Fatty Acid (TcN.sub.2 S.sub.2 FA) Complex and Its Evaluation as a Myocardial Imaging Agent") have disclosed attempts to image normal myocardium utilizing fatty acids with technetium-99m (.sup.99 mTc).
The discovery of specific estrogen receptors in breast carcinoma has led to work in the radiolabeling of various steroids, e.g., estrogens or derivatives thereof, e.g., estradiols. It is believed that a radiolabeled estrogen may be able to indicate receptor levels and help determine types and levels of therapy for breast carcinoma. In this regard, Jagoda et al., (J. Nucl. Med., 1984, 25, p. 472-7, "[.sup.125 I]-17-Iodovinyl 11-Methoxyestradiol: In vivo and In vitro Properties of a High Affinity Estrogen-Receptor Radiopharmaceutical") have studied .sup.125 I labeled methoxy estradiol for such diagnostic uses.
Gibson et al. (Biochem Pharm., Vol. 32, No. 12, p. 1851-56, 1983, "Differences in Affinities of Muscarinic Acetylcholine Receptor Antagonists for Brain and Heart Receptors" and J. Nucl. Med., Vol. 25, No. 2, p. 214-222, February 1984, "The Characteristics of I-125 4-IQNB and H-3QNB In vivo and In vitro") have studied the substrates for muscarinic receptors, e.g. 3-quinuclidinyl benzilate (QNB) and derivatives thereof, radiolabeled with .sup.125 I and .sup.3 H in heart and brain tissue.
As reported by Martin et al. ("Enhanced Binding of the Hypoxic Cell Marker [.sup.3 H] Fluoromisonidazole", J. Nucl. Med., Vol 30, No. 2, 194-201 (1989)) and Hoffman et al. ("Binding of the Hypoxic Tracer [H-3] Misonidazole in Cerebral Ischemia", Stroke, 1987, 18, 168), hypoxia-mediated nitro-heterocyclic groups (e.g., nitroimidazoles, and derivatives thereof) are known to be retained in tissue in the body which is hypoxic, i.e., deficient in oxygen. Hypoxic tissue in the brain or heart typically follows ischemic episodes produced by, for example, arterial occlusions or by a combination of increased demand and insufficient flow. Additionally, Koh et al., (J. Nucl. Med., 1989, 30, p. 789, "Hypoxia Imaging of Tumors Using [F-18]Fluoromisonidazole") have attempted diagnostic imaging of tumors using a nitroimidazole radio labeled with .sup.18 F.
The above-mentioned attempts at diagnostic imaging with various radiolabeled biochemically active groups have provided less than ideal results to this point. For example, the positron emitting isotopes are cyclotron produced and require expensive equipment for imaging which is not widely available. Similarly, .sup.123 I has a thirteen hour half life and is expensive to produce. Further, the .sup.99 mTc complexes with fatty acids have not demonstrated the characteristics of the free fatty acids in myocardial uptake. Finally, the tritium labeled nitroimidazoles are beta-emitting nuclides useful only for autoradiographic studies and not suitable for diagnostic imaging.
Radiolabeled complexes of biochemically active groups which retain the biochemical behavior and affinity of such groups, and which are labeled with a suitable, easy-to-use radionuclide would be a useful addition to the art.